Synthesis of Lactams via a Chiral Phosphoric Acid-Catalyzed Aniline Cyclization

The enantioenriched lactams disclosed in this work are synthesized concisely in four steps. In the penultimate reaction, a benzylamine species complexes with a chiral phosphoric acid to produce benzo-fused δ-lactams equipped with an all-carbon quaternary stereocenter. Partial and full reductions were carried out on the ester and amide moieties, and a Suzuki–Miyaura cross-coupling expanded the molecule from the aromatic ring. Finally, our method was successful at a >1 g scale, indicating that the method has important practical use.

I ncreasing antimicrobial resistance and emerging diseases calls for the scientific community to uncover unique molecules and scaffolds.In this pursuit is the need for improved methods to assemble these structurally relevant motifs.One mission of synthesis is to construct molecules that emulate the functions of valuable natural products.However, a pressing problem is the ability of chemists to synthesize these complex compounds, for the sake of unlocking certain coveted properties, due to elaborate stereochemistry and functional groups.Consequently, chemists need more tools in their toolbox.This drives the development of methodologies to recreate target moieties such as N-and O-containing heterocycles�along with their specific configuration in space.Concurrently, there is considerable literature acknowledging the importance of lactams and their presence in compounds with biological applications.−4 The method herein produces enantioenriched lactams with a chiral center α to the carbonyl through a desymmetrization via a chiral phosphoric acid (CPA) catalyst.The compounds in Figure 1 highlight the importance of the fused lactam motif. 5hiral aryl lactams and their derivatives fulfill key roles as components of drugs and other bioactive natural products. 6urthermore, a review by Roughly and Jordan investigated the types of reactions employed in the pursuit of drug candidates; the category titled "heterocycle formation" was dominated by N-containing heterocycle syntheses. 7Additionally, FDA databases disclose that approximately 60% of unique smallmolecule drugs contain N-based heterocycles. 8Categorically, δ-lactams have received less attention as potential drugs than βand γ-lactams; 9 this presents an opportunity to develop more efficient methods to make them more accessible.The synthetic strategy revealed in this work addresses a gap in desymmetrization and lactamization methodologies.While reports of lactamization techniques exist, 10−13 metal-free enantioselective lactamization methods are scarce.−19 Although metal-driven systems have accomplished impressive chemistry, metals are accompanied by challenges like high price, toxicity, pollution, waste treatment complications, and product contamination. 20Thus, it is attractive to explore organocatalytic options.Sumiyoshi et al. built on nonselective methodologies 21 to synthesize chiral γ-lactams 22 (entry B, Scheme 1).When compound 8 was exposed to (S)-TRIP (50 mol %), γ-lactams (9) were fashioned with ee's ranging from 49% to 66%.While modest ee's are observed, a major limitation is the utilization of 0.5 equiv of the chiral phosphoric acid TRIP, which is impractical on a moderate to large scale.Additionally, a limited substrate scope is explored.In entry C 23 (Scheme 1), lactam 13 is prepared such that the stereocenter is previously established in precursor 12 before the heterocycleforming step.While a chiral lactam is produced, its synthesis requires more than one step.Other published syntheses yield enantioenriched lactams, but the systems either are only diastereoselective (not enantioselective) 24 or do not contain a chiral center on the lactam ring. 25his study harnesses (R)-TRIP at only 5 mol % catalyst loading and produces δ-lactams with ee's up to 75%.Our precursor amine 14 can be cyclized as a primary amine or secondary amine to yield lactam 15 (entry D, Scheme 1).The products contain substitution on the aromatic ring at the ortho, meta, and para positions with halogens, electrondonating groups, and electron-withdrawing groups.These enantioenriched lactams are synthesized in four steps; the concluding step is a metal-free desymmetrization catalyzed by the chiral Brønsted acid TRIP (3,3′-bis(2,4,6-triisopropylphen-yl)-1,1′-binaphthyl-2,2′-diyl hydrogen phosphate), a CPA catalyst.This desymmetrization is elegant because it simultaneously forms a benzo-fused δ-lactam while establishing an all-carbon quaternary chiral center and does not rely on transition-metal catalysts or previously set chiral centers.The remaining ester handle and select substituents on the aromatic ring allow for further functionalization.Besides the readily available starting materials and straightforward reaction conditions, another attractive feature is the ability to generate a vast number of substrates through variation of the nitrobenzyl bromide species, the R group at the α-carbon, and the use of primary or secondary aniline nitrogen nucleophiles.This current desymmetrization strategy was motivated by previous work in the Petersen group on the cyclization of hydroxy-esters to form lactones 17 (entry E, Scheme 1). 26,27Though we draw inspiration from a previous strategy, we are excited to establish a new methodology to synthesize significantly more challenging nitrogen-based heterocycles.

■ RESULTS AND DISCUSSION
Malonate esters provide a scaffold to conduct desymmetrization reactions in the pursuit of chiral lactams (14 to 15, entry D, Scheme 1).Our general strategy began with the alkylation of di-tert-butyl malonate with bromide 18 (Scheme 2).A second alkyl group (e.g., via methyl iodide) is added to 19, giving the dialkylated product 20 (Scheme 2).The nitro group of 20 is hydrogenated to yield a free primary amine 14, which is poised to undergo an intramolecular cyclization reaction at a carbonyl carbon.We hypothesize that resonance with the aromatic ring moderates the reactivity of the nitrogen, allowing it to be an ideal nucleophile for this desymmetrization.Consult the Supporting Information for compound numbering details.
The optimization process began with evaluating the cyclization of aniline 14aa in the presence of various CPAs (Figure 2) to determine which CPA provided the best The Journal of Organic Chemistry enantiomeric enrichment (Table 1, entries 1−7).Initial results indicated that catalyst 21a yielded the best enantioselectivity (50% ee, entry 1, Table 1) at 10 mol % and was utilized for evaluating all subsequent reaction variables.Other catalysts such as 21c, 21d, and 21e showed good reactivity but little enantioselectivity (Table 1, entries 3−5).Catalysts 21b, 21f, and 21g showed some enantioenrichment of product but lacked the desired reactivity (Table 1, entries 2, 6, and 7).It is known that modifying the BINOL backbone of the CPA can tune the electronics and solubility of the catalyst. 28,29As seen in previous systems, this has various effects on experimental outcomes. 30,31n examination of other nonpolar solvents (entries 8−11, Table 1) showed that toluene facilitated the best enantioenrichment, improving the ee of lactone 15aa from 50% to 67% (compare entries 1 and 11, Table 1).Hexanes (entry 8, Table 1) also performed favorably.We hypothesize that the hydrophobicity of these two solvents drives the substrate and the catalyst into closer proximity to interact more successfully.Polar solvents were not examined here after previous work within the group determined that polar solvents interfered with the binding abilities of 21a. 26,27luting the reaction concentration to 0.0025 M (with 10 mol % of 21a) improved the ee to 72% while still providing a yield of 99% (entry 15, Table 1).Lowering the catalyst loading to 5 mol % and concentration to 0.0025 M provided the best ee of 73% while maintaining a 97% yield (entry 16, Table 1).While comparable ee's were achieved with a 1 mol % catalyst loading (entries 18 and 20, Table 1), yields suffered even when the reactions were allowed to run up to 7 days.However, it was discovered that heating the reaction to 50 °C with 1 mol % 21a enabled the reaction to run to completion with minimal decrease in ee (entry 19, Table 1).While we were able to salvage yield at 50 °C (entry 19), 5 mol % still offered better selectivity over 1 mol % (entries 16 and 17 vs entries 18−20) without requiring any heat and performed as well as 10 mol %, so we proceeded with the lower loading.Surprisingly, reducing the temperature to 0 °C (entry 12, Table 1) or subzero (entry 23, Table 1) did not improve the ee.In fact, −20 °C conditions resulted in remarkably lower ee and yield (entry 23, Table 1).The more dilute concentration afforded a slightly better ee (entries 15 and 16, Table 1).However, a 0.0025 M concentration is not convenient nor environmentally friendly on a practical scale.Therefore, while entry 16 afforded the best conditions technically (Table 1), the conditions that were used for the subsequent substrate scope were 0.025 M toluene with 5 mol % catalyst 21a at room temperature for 3 days.
DFT studies confirm a dual-binding activation mode (Figure 3), which occurs within a small "active site" where the substrate is engulfed by the bulky triisopropylphenyl groups.The Lewis base portion of 21a hydrogen bonds with an amine proton, while the Brønsted acid portion of 21a hydrogen bonds with the carbonyl oxygen of one of the esters (Figure 3a).These interactions intensify the nucleophilicity of the nitrogen and the electrophilicity of the carbonyl carbon.The Brønsted acid hydrogen (red) is concertedly transferred to the carbonyl oxygen as the C−N lactam bond is established.The triisopropylphenyl groups and the axial chirality of the catalyst direct the cyclization to occur in one preferred direction.The tetrahedral intermediate of the heterocycle collapses, producing a δ-lactam with a positively charged nitrogen.Finally, the abstraction of the hydrogen on the nitrogen (green) to regenerate the CPA catalyst is barrierless (Figure 3a).More detailed DFT calculations were conducted to examine the C− N bond-forming step for both enantiomers.Formation of the S enantiomer of 15aa follows a bidentate route, while the R enantiomer takes a monodentate route, leading to barrier heights of 9.89 and 16.74 kcal/mol for S and R, respectively (Figure 3b).These calculations demonstrate how the cyclization for the S enantiomer follows a more energetically favorable pathway than the R enantiomer.Full coordinates of this process are included in the Supporting Information.These data are consistent with previous DFT studies on similar desymmetrizations and kinetic resolutions. 32All calculations were performed with the Gaussian 16 C01 package with ultrafine grids and tight self-consistent-field convergence. 33tructures were optimized using the DFT M06-2X exchangecorrelation energy density functional. 34The basis set was triple-ζ 6-311+G(d) for N, O, and P elements and 6-31G(d) for C and H elements. 35 Toluene was the solvent included in the calculations with the CPCM 36 implicit solvent model employed.
We embarked on the substrate scope with the intent of showcasing the method's versatility.Various alkylating groups and aryl electron-withdrawing groups and electron-donating The Journal of Organic Chemistry groups were tested to determine what complimented or inhibited the system (Figure 4).The reactivity and resultant ee's were not significantly impacted by the electronics of the various groups on the aniline ring.Substituents at the meta and para positions to the amine on the aromatic ring do not affect the efficacy of the reaction (15cb−15fa, Figure 4).We hypothesize that substrate 15ba suffered lower enantioenrichment due to steric interference of the ortho-methyl group on the amine.
Generally, any alkyl moiety at the α-carbon was well tolerated.Bulkier groups like an isopropyl or sec-butyl (15ac and 15ad, Figure 4) can be attached without significant negative impacts being observed.The presence of the heteroatom in the alkylating chain (at the α-carbon) resulted in a significantly lower ee (23%), while a high yield (96%) was retained (15af).We theorize that the oxygen atom interrupts the hydrogen bonding network between catalyst and substrate.We validated that the di-tert-butyl esters were optimal for cyclization by preparing the less bulky diisopropyl ester.Upon hydrogenating the dialkylated diisopropyl malonate to the amine, a sizable portion cyclized spontaneously in situ to form the racemic lactam (23aa).Uncyclized amine underwent spontaneous cyclization, even when material was stored at 4−5 °C.We then prepared and cyclized secondary amines to manufacture lactams with a methylated nitrogen (Figure 4, compound 22aa).The synthetic route to the secondary amines was analogous to that of the primary amines.We were excited to produce 22aa with 75% ee from a secondary amine subjected to 5 mol % 21a.Consult Scheme S1 in the SI for the full synthetic route.
The absolute configuration of lactam 15aa was determined to be S via X-ray crystallography.All other lactams were assigned based on analogy.Consult the SI for details on the crystal growth method.
Moreover, we can show that recrystallization of lactams leads to improved enantioenrichment with satisfactory recovery of mass.Several recrystallization attempts were conducted (entries 1−6, Table 2) before obtaining crystals with 87% ee in 60% recovery (entry 6, Table 2).The enantioselective recrystallization was an exercise in balance; some entries provided excellent ee with very poor recovery (entry 3), while others had good recovery but only marginally improved the ee (entry 4).Fortunately, in all cases, we could reconcentrate the mother liquor to recover all of the material to attempt a better recrystallization.We felt that 0.43 g of crystals with 87% ee was satisfactory.These results do show, however, that it is possible to obtain enantiomerically pure crystals.
Additionally, while the reactions for the substrate scope (Figure 4) were performed on a 100 mg scale with 5 mol % Base conditions: 10 mol % of 21a, 0.025 M in 1,2-DCE, stirring for 3 days at rt. b qNMR yields based on 1 H NMR analysis using 1,3,5trimethoxybenzene as an internal standard.c % ee values obtained via HPLC analysis.d Opposite enantiomer was formed per HPLC analysis.e Conditions giving the best results based first on % ee and then % yield.All optimization reactions conducted on a 10 mg scale.The full optimization table can be seen in the SI.21a, our method can be adapted to larger scale (>1 g) with lower catalyst loading (2 mol % 21a).The model substrate 14aa was subjected to a cyclization in toluene at 0.025 M at 50 °C with 2 mol % 21a.This large-scale lactamization gave 15aa in 96% yield and 75% ee (1.05 g, 4.00 mmol) from 1.40 g (4.17 mmol) of 14aa, as depicted in Scheme 3.
To demonstrate the applicability and practical usefulness of the chiral lactam products, we have conducted further manipulations on select substrates (Scheme 4).These transformations are relevant because they can expand the molecule so that it fits the needs of specific targets or can emulate valuable bioactive motifs.The remaining ester moiety in compound 15aa can be reduced to yield an aldehyde 26, or the lactam can be further reduced to give a 6-membered amine heterocycle 27.Alternatively, incorporation of a halogen in the aniline ring as seen in substrates 15ea and 15eb allows for potential coupling reactions.Highlighting this use, we were able to perform a Suzuki−Miyaura coupling 37 of 15ea and 4-

■ CONCLUSION
We have reported an elegant methodology to synthesize benzo-fused δ-lactams in yields up to 96% and enantiomeric excess up to 75% through the desymmetrization of disubstituted malonic esters in the presence of a chiral Brønsted acid organocatalyst.Benzo-fused δ-lactams are seen in an array of valuable compounds; accessing this motif through our methodology will significantly aid in the ability to synthesize these compounds or necessary analogues.To the best of our knowledge, this is the first enantioselective Brønsted acid-catalyzed lactamization resulting in benzofused δ-lactams.Properly harnessing nitrogen as a nucleophile is challenging; nitrogen can be nonreactive, too basic (deprotonating the catalyst and killing reaction), or too nucleophilic (attacking the carbonyl too rapidly and foregoing selectivity).We found that an aniline nitrogen maintained a satisfactory balance between nucleophilicity and reactivity.The substrate scope allows for diversification in structure, which lends to variation in how each lactam can be subsequently utilized.Both primary and secondary amines can successfully complex with TRIP to produce enantioenriched δ-lactams and N-methylated δ-lactams.The substrates can be further manipulated via reductions or a coupling reaction.This lactamization strategy can also be scaled up; merely 2 mol % 21a can achieve 75% ee and 96% yield on a >1 g scale.We expect that the work reported will provide a facile and efficient means for chemists to produce desired molecules.

■ EXPERIMENTAL DETAILS
General Methods.Unless noted, all solvents and reagents were obtained from commercial sources and used without further purification; anhydrous solvents were dried following standard procedures.Compounds 18a−18e were purchased from a chemical supplier (1PlusChem, TCI, Sigma-Aldrich, or Chemcia Scientific, LLC); compound 18f was synthesized by brominating 5-methoxy-2nitrotoluene (please consult the Supporting Information for a full compound numbering guide).Purity and identity analysis was conducted on compound 18b.The 1 H and 13 C (proton decoupled) nuclear magnetic resonance (NMR) spectra were plotted on a 400 MHz spectrometer using CDCl 3 and acetone-d 6 as solvents at room temperature.The NMR chemical shifts (δ) are reported in parts per million.Abbreviations for 1 H NMR: s = singlet, d = doublet, m = multiplet, br s = broad singlet, t = triplet, q = quartet, sept = septet, hept = heptet, dd = doublet of doublets, dt = doublet of triplets, td = triplet of doublets, dq = doublet of quartets.The reactions were monitored by TLC using silica G F254 precoated plates.Flash chromatography was performed using flash-grade silica gel (particle size 40−63 μm, 230 × 400 mesh).Enantiomeric excess was determined by HPLC analysis.High-resolution mass spectra were acquired on an Orbitrap XL MS system.The specific rotations were acquired on an analytical polarimeter.
General Method for Quantitative NMR. 1 H NMR was used to quantify yields for the optimization table reactions (10 mg scale).After the cyclization reaction of amine 14aa with catalyst 21a, the reaction mixture was concentrated.Crude lactam 15aa was diluted with CDCl 3 and added to an NMR tube.An internal standard solution of 1,3,5-trimethoxybenzene in CDCl 3 was prepared.A known amount of internal standard solution was added to the NMR tube containing product 15aa.The most shielded aromatic peak of 15aa was compared to the aromatic singlet of the internal standard.Stoichiometric calculations in an Excel spreadsheet revealed the percent yield based on the integrations of the peaks, how many protons each peak represented, and theoretical yield for each specific reaction and spectrum.
The crude oil residue was purified by flash chromatography on silica gel (5% → 15% EtOAc in hexanes) to afford compound 20fa as a white powdery solid (1.2 g, 53% yield). 1  Compound 20aa.To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 370 mg, 9.2 mmol) in DMF (12 mL) was made.Compound 19a (1.6 g, 4.6 mmol) was then added slowly at 0 °C.After the ceasing of gas evolution, methyl iodide was added (0.36 mL, 5.8 mmol).The reaction was stirred at 40 °C under argon for 16 h.The reaction was quenched with 12 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate (3 × 15 mL).The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo.The oil residue was purified by flash chromatography on silica gel (5% → 25% EtOAc in hexanes) to afford compound 20aa as a clear, pale-yellow oil (1.5 g, 89% yield). 1  Compound 20ab.To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 110 mg, 7.8 mmol) in DMF (13 mL) was made.Compound 19a (1.5 g, 4.3 mmol) was then added slowly at 0 °C.After the ceasing of gas evolution, ethyl iodide was added (1.2 mL, 3.9 mmol).The reaction was stirred at 40 °C under argon for 16 h.The reaction was quenched with 14 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate (3 × 15 mL).The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo.The oil residue was purified by flash chromatography on silica gel (5% → 25% EtOAc in hexanes) to afford compound 20ab as a light-yellow powder (1.4 g, 92% yield).20ab was taken on to the next step without characterization (see compound 14ab).
Compound 20ac.To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 320 mg, 7.9 mmol) in THF (30 mL) was made.Compound 19a (2.2 g, 6.3 mmol) was then added slowly at 0 °C.After the ceasing of gas evolution, 2-iodopropane was added (1.3 mL, 13 mmol).The reaction was stirred at 40 °C under argon for 16 h.The reaction was quenched with 30 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate (3 × 15 mL).The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo.The oil residue was purified by flash chromatography on silica gel (5% → 25% EtOAc in hexanes) to afford compound 20ac as a clear, pale-yellow oil (1.7 g, 69% yield).20ac was taken on to the next step without characterization (see compound 14ac).
Compound 20ad.To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 290 mg, 6.3 mmol) in DMF (20 mL) was made.Compound 19a (1.1 g, 3.1 mmol) was then added slowly at 0 °C.After the ceasing of gas evolution, 1-bromo-2methylpropane was added (0.60 mL, 3.8 mmol).The reaction was stirred at 40 °C under argon for 16 h.The reaction was quenched with 20 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate (3 × 15 mL).The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo.The oil residue was purified by flash chromatography on silica gel (2% → 20% EtOAc in hexanes) to afford compound 20ad as a pale-yellow oil (780 mg, 61% yield).20ad was taken on to the next step without characterization (see compound 14ad).
Compound 20ae.To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 310 mg, 7.7 mmol) in DMF (13 mL) was made.Compound 19a (1.3 g, 3.9 mmol) was then added slowly at 0 °C.After the ceasing of gas evolution, benzyl bromide was added (0.55 mL, 4.6 mmol).The reaction was stirred at 40 °C under argon for 16 h.The reaction was quenched with 14 mL of a 1:1 10%

The Journal of Organic Chemistry
HCl and water solution and was extracted with ethyl acetate three times (3 × 15 mL).The combined organic layers were dried over MgSO 4 , filtered and concentrated in vacuo.The oil residue was purified by flash chromatography on silica gel (5% → 25% EtOAc in hexanes) to afford compound 20ae as a clear, yellow oil (1.4 g, 87% yield).20ae was taken on to the next step without characterization (see compound 14ae).
Compound 20af.To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 230 mg, 5.7 mmol) in DMF (10 mL) was made.Compound 19a (1.0 g, 2.9 mmol) was then added slowly at 0 °C.After the ceasing of gas evolution, 1-bromo-3methoxypropane was added (0.35 mL, 3.1 mmol).The reaction was stirred at 40 °C under argon gas for 16 h.The reaction was quenched with 10 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate (3 × 10 mL).The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo.The oil residue was purified by flash chromatography on silica gel (5% → 25% EtOAc in hexanes) to afford compound 20af as a yellow oil (1.1 g, 90% yield).20af was taken on to the next step without characterization (see compound 14af).
Compound 20ba.To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 160 mg, 3.9 mmol) in DMF (10 mL) was made.Compound 19b (710 mg, 1.9 mmol) was then added slowly at 0 °C.After the ceasing of gas evolution, methyl iodide was added (0.13 mL, 2.1 mmol).The reaction was stirred at 40 °C under argon for 16 h.The reaction was quenched with 10 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate (3 × 10 mL).The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo.The oil residue was purified by flash chromatography on silica gel (5% → 25% EtOAc in hexanes) to afford compound 20ba as a clear, pale-yellow oil (650 mg, 88% yield).20ba was taken on to the next step without characterization (see compound 14ba).
Compound 20cb.To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 140 mg, 3.4 mmol) in DMF (8 mL) was made.Compound 19c (510 mg, 1.4 mmol) was then added slowly at 0 °C.After the ceasing of gas evolution, ethyl iodide was added (0.22 mL, 2.7 mmol).The reaction was stirred at 40 °C under argon for 16 h.The reaction was quenched with 8 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate three times (3 × 10 mL).The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo.The oil residue was purified by flash chromatography on silica gel (5% → 25% EtOAc in hexanes) to afford compound 20cb as a yellow oil (430 mg, 80% yield).20cb was taken on to the next step without characterization (see compound 14cb).
Compound 20ea.To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 250 mg, 6.2 mmol) in DMF (12 mL) was made.Compound 19e (1.2 g, 3.1 mmol) was then added slowly at 0 °C.After the ceasing of gas evolution, methyl iodide was added (0.21 mL, 3.4 mmol).The reaction was stirred at 40 °C under argon for 16 h.The reaction was quenched with 12 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate (3 × 15 mL).The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo.The oil residue was purified by flash chromatography on silica gel (5% → 25% EtOAc in hexanes) to afford compound 20ea as a clear, yellow oil (1.1 g, 86% yield).20ea was taken on to the next step without characterization (see compound 14ea).
Compound 20eb.To a flame-dried round-bottom flask, a solution of sodium hydride (60% dispersion, 230 mg, 5.6 mmol) in DMF (12 mL) was made.Compound 19e (1.1 g, 2.8 mmol) was then added slowly at 0 °C.After the ceasing of gas evolution, ethyl iodide was added (1.1 mL, 3.4 mmol).The reaction was stirred at 40 °C under argon for 16 h.The reaction was quenched with 12 mL of a 1:1 10% HCl and water solution and was extracted with ethyl acetate (3 × 15 mL).The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo.The oil residue was purified by flash chromatography on silica gel (5% → 30% EtOAc in hexanes) to afford compound 20eb as a clear, yellow oil (790 mg, 68% yield).
20eb was taken on to the next step without characterization (see compound 14eb).

Data Availability Statement
The data underlying this study are available in the published article and its Supporting Information.

Figure 1 .
Figure 1.Significance of the chiral lactams produced in this work is highlighted by the featured lactam-containing compounds.

Scheme 1 .
Scheme 1. Literature Precedence, Other Lactamization Strategies, and Reaction Scheme for the Current Study a

Table 2 .
Summary of Results from Recrystallization Study